Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy via the VCL Gene

Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle characterized by idiopathic hypertrophy of the left ventricle, although hypertrophy of the right ventricle may occur occasionally (Fifer and Vlahakes Circulation 117:429-439, 2008). HCM is distinguished by an extensive clinical variability between individuals with regards to the age of onset, pattern and extent of hypertrophy, and prognosis. Symptoms include dyspnea, exercise intolerance, chest pain, palpitations, arrhythmia, atrial fibrillation, syncope, and sudden death (Maron et al. N Engl J Med 316:780-789, 1987). Additional features include left ventricular outflow tract obstruction, which is associated with increased risk for heart failure and cardiovascular death (Ommen et al. J Am Coll Cardiol 46:470-476, 2005). HCM affects 1 in 500 people worldwide (Maron et al. Circulation 92:785-789, 1995).

Dilated cardiomyopathy (DCM) is a heterogeneous disease of the heart muscle. It is characterized by dilatation of the left, right, or both ventricles, systolic dysfunction, and diminished myocardial contractility. Symptoms include arrhythmia, dyspnea, chest pain, palpitation, fainting, and congestive heart failure (Ikram et al. Br Heart J 57:521-527, 1987). Additional features may include woolly hair and myopathy (Moller et al. Eur J Hum Genet 17:1241-1249, 2009). Sudden death occurs in ~30% of patients with DCM (Tamburro and Wilber Am Heart J 124:1035-1045, 1992). Although symptoms of DCM usually begin in adulthood, an extensive clinical variability between individuals concerning the age of onset and the extent of structural and functional abnormality has been documented. The prevalence of DCM has been estimated at ~1/2700 (Codd et al. Circulation 80:564-572, 1989).

HCM is a heterogeneous genetic disease that is inherited in an autosomal dominant manner. It is caused by variants in various genes, most of which encode sarcomeric proteins. Defects in 12 genes: MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, CSRP3, TTN, MYH6, and TCAP account for approximately 90% of HCM cases that have detectable variants (Cirino and Ho, GeneReviews, 2009). In addition to these 12 genes, several genes have been shown to be rarely mutated in HCM patients. These include the VCL gene. To date, one missense variant in exon 7 of the VCL gene (p.Leu277Met) was reported in a patient with severely obstructive, mid-ventricular hypertrophy (Vasile et al. Biochem Biophys Res Commun 345:998-1003, 2006). VCL variants have also been reported in patients with dilated cardiomyopathy (DCM) (Olson et al. Circulation 105:431-437, 2002). The VCL gene encodes vinculin, a cytoskeletal protein involved in anchoring F-actin to the membrane.

This test allows the detection of variants in rare cases of HCM and DCM patients (Hershberger et al. Circ Heart Fail 2:253-261, 2009).

This test provides full coverage of all coding exons of the VCL gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).